The present invention relates to processes and intermediates employed in the synthesis of HIV protease inhibitors.
Compounds that are inhibitors of human immunodeficiency virus (HIV) protease are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting an HIV infection. Examples of HIV protease inhibitors include the compound of formula I: 
which is also known as ((2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)-amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane or lopinavir. Processes for preparing compounds of formula I and analogs thereof are provided in U.S. Pat. No. 5,914,332, issued Jun. 22, 1999, which is herein incorporated by reference.
An intermediate which is useful for preparing the compounds of formula I and analogs thereof is a compound of formula II: 
wherein R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl and P1 and P2 are independently selected from hydrogen and an N-protecting group. Preferred compounds of formula II are those wherein R3 is loweralkyl, P1 and P2 are hydrogen or P1 and P2 are benzyl. More preferred compounds of formula II are those wherein R3 is isopropyl and P1 and P2 are hydrogen or wherein R3 is is isopropyl and P1 and P2 are benzyl.
Methods for the preparation of a compound of formula II are disclosed in U.S. Pat. No. 5,914,332. These methods involve the reaction of a compound of the formula III: 
wherein P1 is hydrogen or an N-protecting group and P2 is an N-protecting group With a compound of the formula IV: 
wherein R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl; or a salt or an activated ester thereof.
Preferred compounds of the formula III are those wherein P1 and P2 are N-protecting groups. Most preferred compounds of the formula III are those wherein P1 and P2 are both benzyl. Most highly preferred is the compound of formula III that is (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane.
Preferred compounds of the formula IV are those wherein R3 is loweralkyl. Most preferred compounds of the formula IV are those wherein R3 is isopropyl. Also preferred are the acid chloride derivatives of the compounds of formula IV. Most highly preferred is the compound of formula IV that is 2S-(1-tetrahydro-pyrimid-2-only)-3-methyl butanoic acid and the compound of formula IV that is 2S-(1-tetrahydro-pyrimid-2-only)-3-methyl butanoyl chloride.
In the disclosed process, (2S,3S,5S)-2-N,N-dibenzylamino-3-hydroxy-5-amino-1,6-diphenylhexane is reacted with 2S-(1-tetrahydro-pyrimid-2-only)-3-methyl butanoyl chloride in a suitable solvent (ethyl acetate or ethyl acetate/DMF) with imidazole as a base. However, this process is not suited for large-scale production for many reasons, including unstable intermediates, low yields, and catalyst poisoning. In particular, the acid chloride is relatively unstable and the use of thionyl chloride to prepare the acid chloride leads to impurities that poison the catalyst used in a later reaction. In addition, some racemization of the amino acid side chain occurs under the reaction conditions used.
Thus, there is a continuing need for improved processes for preparing intermediates employed in the synthesis of HIV protease inhibitors, including compounds of formula I as defined hereinabove.
The present invention relates to processes and intermediates for preparing a compound of formula II: 
wherein R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl and P1 and P2 are independently selected from hydrogen and an N-protecting group comprising reacting a compound of the formula III: 
wherein P1 is hydrogen or an N-protecting group and P2 is an N-protecting group with a compound of the formula V: 
wherein R3 is loweralkyl, hydroxyalkyl or cycloalkylalkyl and R4 is a nitrogen-containing heterocycle, bonded through a ring nitrogen atom to the carbonyl group, selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, indolyl, benzimidazolyl and benzotriazolyl.
In a preferred process of the invention, P1 and P2 are N-protecting groups, R3 is loweralkyl and R4 is imidazolyl. In a most preferred process of the invention, P1 and P2 are both benzyl, R3 is isopropyl and R4 is imidazolyl.
In the process of the invention, the compound of formula III is reacted with the compound of formula V in a molar ratio of from about 1.0 moles of the compound of formula III to about 1.3 moles of the compound of formula V. A preferred ratio is from about 1.0 to about 1.2. A most preferred ratio is from about 1.0 to about 1.15.
Suitable solvents for the process of the invention are inert solvents, such as isopropyl acetate, ethyl acetate, tetrahydrofuran (THF), methyl t-butyl ether and the like. A preferred solvent for the process of the invention is ethyl acetate.
The process of the invention can be carried out at a temperature of from about 15xc2x0 C. to about 100xc2x0 C. The preferred temperature for the process of the invention is about the reflux temperature of the solvent. The most preferred temperature for the process of the invention is from about 75xc2x0 C. to about 80xc2x0 C.
The process of the invention is accelerated by the presence of water. The preferred amount of water present in the reaction mixture is from about 1% to about 3% (weight/volume), based on the ratio of the amount of water (in grams) to the total volume (in mL) of the reaction mixture.
The compound of formula V is prepared by reaction of carboxylic acid IV (about 1.00 moles) with carbonyldiimidazole (about 1.05 moles) in an inert, aprotic solvent such as isopropyl acetate, ethyl acetate, tetrahydrofuran (THF), methyl t-butyl ether and the like at a temperature of from about 15xc2x0 C. to about 50xc2x0 C. Preferably, carboxylic acid IV is reacted with R4xe2x80x94C(O)xe2x80x94R4, R4xe2x80x94C(S)xe2x80x94R4 or R4xe2x80x94S(O)xe2x80x94R4 wherein R4 is defined as above (preferably, carbonyldiimidazole) in ethyl acetate at about 15xc2x0 C.
While the compound of formula V can be isolated, preferably it is prepared and then reacted (without isolation and purification) with the compound of formula III in a one-pot process.
The compound of formula II wherein P1 and P2 are each benzyl can then be debenzylated and the resulting compound of formula II wherein P1 and P2 are each hydrogen (as the (S)-pyroglutamic acid salt) can be reacted with 2,6-dimethylphenoxyacetyl chloride (as disclosed in U.S. Pat. No. 5,914,332) to provide lopinavir.
The term xe2x80x9cloweralkylxe2x80x9d as used herein refers to straight or branched chain hydrocarbon radicals containing from 1 to 6 carbon atoms. Representative examples of loweralkyl groups include groups such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.
The term xe2x80x9c(cycloalkyl)alkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a loweralkyl radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl (phenyl-Sxe2x80x94), triphenylmethylsulfenyl (trityl-Sxe2x80x94) and the like; sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)xe2x80x94), t-butylsulfinyl (t-Bu-S(O)xe2x80x94) and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, benzyloxymethyl and the like; p-methoxyphenyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups include benzyl and the like.